In response to pro-atherosclerotic factors such as oxidized lipids, or to therapeutic interventions such as angioplasty, stents, or bypass surgery, vascular smooth muscle cells (VSMC) migrate to the intima, resulting in intimal hyperplasia, restenosis, graft failure, or atherosclerosis. Understanding the mechanisms involved in VSMC migration has been a major focus of biomedical research. Our exciting preliminary data show that in response to or wire-mediated carotid artery injury, increased expression of autophagy-related (Atg) proteins is associated with increased VSMC migration and intimal hyperplasia. Pharmacological and genetic suppression of autophagy inhibits VSMC migration. Mechanistically, suppression of vascular autophagy leads to the accumulation of amino acid synthesis protein 5 (GCN5), a ubiquitous histone acetyltransferase (HAT) that promotes transcriptional activation. Furthermore, we found that GCN5 accumulation is associated with increased ?-tubulin acetylation, microtubule stabilization, and inhibition of VSMC migration. The central hypothesis is that autophagy-dependent degradation of GCN5 promotes VSMC migration via inhibition of ?-tubulin acetylation. This hypothesis will be tested using gain-/lossof-function strategies in both animal models and cultured cells.
Aim 1 will determine the role of autophagy in regulating VSMC migration in response to vascular injury in vivo by characterizing the spatial and temporal dynamics of vascular autophagy, VSMC migration, and neointimal hyperplasia using smMHC/eGFP transgenic mice, determining whether autophagy deficiency inhibits VSMC migration and neointimal formation in response to carotid ligation and/or vascular injury using Beclin1 heterozygous mice (beclin1+/-), and examining whether enhanced VSMC autophagy promotes VSMC migration and exacerbates neointimal hyperplasia and atherosclerosis in response to vascular injury in Atg7 SMC-specific transgenic mice (Atg-TG). In addition, the role of autophagy in regulating VSMC migration will be determined using gain- and loss-of-function approaches in cultured aortic rings and VSMCs.
Aim 2 is to delineate the mechanism by which autophagy promotes VSMC migration. By test the hypothesis that autophagy promotes VSMC migration by enhancing GCN5 degradation and reducing ?-tubulin acetylation. The proposed study will characterize the molecular mechanism by which autophagy degrades GCN5 in VSMCs, examine whether GCN5 acetylates ?-tubulin and stabilizes microtubules, and determine whether autophagy suppression inhibits VSMC migration by increasing GCN5-mediated acetylation of ?-tubulin in beclin+/- mice of wire-mediated carotid artery injury, carotid ligation, and atherosclerosis, and Apoe-/-/beclin1+/- mice fed with a high-ft diet.
The goal of this new application is to establish the essential roles of autophagy in controlling vascular smooth muscle migration, a critical event in the initiation and progression of proliferative vascular diseases such as atherosclerosis, hypertension, restenosis after angioplasty or bypass, and diabetic vascular complications. The proposed project has the potential to provide a foundation for new directions in basic research and identify novel targets for the treatment and prevention of proliferative vascular diseases, atherosclerosis, and vascular complications in diabetes.
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